Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.
Level 2 - randomized trial
Individual randomized controlled trial
PubMed 12117397 · doi:10.1001/jama.288.3.321
What was done
In the Women's Health Initiative randomized controlled primary prevention trial, 16,608 postmenopausal women aged 50-79 years with an intact uterus were recruited across 40 US clinical centers from 1993 to 1998. Participants received daily oral conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) in one tablet (n = 8,506) or matching placebo (n = 8,102). The primary outcome was coronary heart disease (nonfatal myocardial infarction and coronary death), and the primary adverse outcome was invasive breast cancer. A global index monitored overall risk-benefit balance.
What was found
The trial was stopped early after a mean follow-up of 5.2 years because invasive breast cancer exceeded the stopping boundary and the global index indicated overall harm. Estimated hazard ratios (nominal 95% confidence intervals) were: coronary heart disease 1.29 (1.02-1.63, 286 cases); invasive breast cancer 1.26 (1.00-1.59, 290 cases); stroke 1.41 (1.07-1.85, 212 cases); pulmonary embolism 2.13 (1.39-3.25, 101 cases); colorectal cancer 0.63 (0.43-0.92, 112 cases); endometrial cancer 0.83 (0.47-1.47, 47 cases); hip fracture 0.66 (0.45-0.98, 106 cases); death due to other causes 0.92 (0.74-1.14, 331 cases); total cardiovascular disease 1.22 (1.09-1.36); total cancer 1.03 (0.90-1.17); combined fractures 0.76 (0.69-0.85); total mortality 0.98 (0.82-1.18); and global index 1.15 (1.03-1.28). Absolute excess risks per 10,000 person-years were 7 more coronary heart disease events, 8 more strokes, 8 more pulmonary embolisms, and 8 more invasive breast cancers, against absolute reductions of 6 fewer colorectal cancers and 5 fewer hip fractures (global index absolute excess risk of 19 per 10,000 person-years).
Why it matters
This trial established that combined estrogen plus progestin increases cardiovascular and breast cancer risks and should not be used for the primary prevention of chronic disease in postmenopausal women.
Limits
The trial examined only one specific oral drug combination and fixed dosage (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate) in postmenopausal women with an intact uterus aged 50-79 years; it does not directly inform other routes, formulations, or estrogen-only regimens. Early termination at 5.2 years precluded assessment over the full planned 8.5-year duration. Symptom relief and quality of life were not reported in the abstract.
Cited by
- supports The Women's Health Initiative stopped an estrogen-based hormone therapy trial early because it was not reducing cardiovascular risk and appeared to increase risk.